Sustained Effect of Delayed-Release Dimethyl Fumarate in Newly Diagnosed Patients with Relapsing–Remitting Multiple Sclerosis: 6-Year Interim Results From an Extension of the DEFINE and CONFIRM Studies

INTRODUCTION: Delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) demonstrated clinical and neuroradiologic efficacy and safety in the Phase 3 DEFINE and CONFIRM trials, and in the extension study (ENDORSE), in patients with relapsing–remitting multiple sclerosis (RRMS). This post hoc analysis assessed DMF efficacy in newly diagnosed patients with RRMS with 6-year minimum follow-up. METHODS: Patients randomized in DEFINE/CONFIRM to DMF 240 mg twice (BID) or thrice daily (TID) continued on same dosage in ENDORSE. Patients randomized to placebo (PBO) or glatiramer acetate (CONFIRM only) were re-randomized to DMF BID or TID. Results for DMF BID (approved dosage) are reported. Newly diagnosed patients were diagnosed within 1 year prior to DEFINE/CONFIRM entry and either treatment-naive or previously treated with corticosteroids alone. RESULTS: The newly diagnosed population included 144 patients continuously treated with DMF BID in DEFINE/CONFIRM and ENDORSE (DMF/DMF) and 85 treated with PBO for 2 years in DEFINE/CONFIRM followed by 4 years of DMF BID in ENDORSE (PBO/DMF). At 6 years (ENDORSE Year 4), the annualized relapse rates [ARR; 95% confidence interval (CI)] were 0.137 (0.101, 0.186) and 0.168 (0.113, 0.252) for DMF/DMF and PBO/DMF, respectively; representing 19% risk reduction (P = 0.3988). PBO/DMF patients demonstrated improvements in ARR after switching to DMF in ENDORSE: 0.260 (0.182, 0.372) for Years 0–2 (DEFINE/CONFIRM) and 0.102 (0.064, 0.163) for Years 3–6 (ENDORSE), representing 61% risk reduction for Years 3–6 versus Years 1–2 (P < 0.0001). The proportion of patients with 24-week confirmed disability progression (95% CI) at 6 years was 15.7% (10.3%, 23.7%) in DMF/DMF and 24.3% (15.9%, 36.2%) in PBO/DMF, representing 49% risk reduction versus PBO/DMF (P = 0.0397). CONCLUSION: Long-term DMF treatment demonstrated strong and sustained efficacy in newly diagnosed patients. Results suggest greater clinical benefits with earlier initiation of treatment in this patient population. FUNDING: Biogen. TRIAL REGISTRATION: ClinicalTrials.gov identifiers, NCT00835770 (ENDORSE); NCT00420212 (DEFINE); NCT00451451 (CONFIRM).